Lewis Base-Catalyzed Interhalogenation of Terminal Allenes: Selective Strategy for Accessing Vicinal Vinylic, Allylic Heterodihalides

Abstract

Though precedent remains limited, the selective interhalogenation of allenes offers a valuable synthetic strategy to access products where each halide exhibits orthogonal reactivity. Here, we describe a Lewis-base catalyzed approach for the dihalogenation (bromochlorination, iodochlorination, iodobromination, and dibromination) of terminal allenes. By employing just 1 mol% of triphenylphosphine oxide or hexamethylphosphoramide to activate thionyl halides in the presence of electrophilic halogenation reagents, we achieve the conversion of monosubstituted allenes to vicinal allylic, vinylic dihalides with up to 93% yield and >20:1 regioisomeric ratio, favoring the branched dihalogenated product. A range of functional groups are tolerated, including nitrile, ester, phosphate, sulfonamide, and silyl groups, and the reaction proved to be scalable. The utility of various dihalide products was investigated in substitution and cross-coupling chemistry, highlighting the distinct reactivity among the different classes.

Graphical Abstract

The utility of organohalides is evident from their widespread use in synthetic chemistry, pharmaceuticals, and agrochemicals.^1,2,3,4 With the continual discovery of bioactive, organohalogen natural products, many of which feature vicinal heterodihalide motifs, designing elegant approaches for the incorporation of halogens into organic frameworks is of increasing importance. Consequently, much progress has been made over the past decade, including recent work by our group, for the preparation of heterodihalides from alkenes and alkynes (Figure 1a).^5,6

Figure 1.

Allene interhalogenation– prevalence, strategy, and limitations

By comparison, the interhalogenation of allenes is hardly developed, despite recent advances in their selective functionalization (Figure 1b).⁷ Further, the utility of the resulting heterodihalide products is apparent when one considers the divergent reactivity profiles innate to allylic and vinylic halides (e.g., nucleophilic displacement, cross coupling chemistry, etc.) and the broad utility of alkenes as synthetic handles. For these reasons, vicinal vinylic, allylic heterodihalides, though underexplored, bear the capacity to serve as prized synthetic lynchpins.

Strategies for allene interhalogenation are generally plagued by issues of regio-, stereo-, and site-selectivity.^{7e, 8} The onerous nature of these transformations is exemplified in the limited number of reports detailing the bromochlorination of allenes (Figure 1b). Two independent examples disclosed the use of BrCl for the bromochlorination of propadiene or 2,3-pentadiene.⁹ However, these reactions suffer from low yields and the presence of solvent incorporated byproducts. In some cases, solvolysis represented the major reaction pathway or no yields were reported altogether, raising concerns as to the overall efficiency of this transformation. During the course of our studies, Katayev and coworkers disclosed a unique transfer dihalogenation strategy applicable to allenes. However, only a singular example of vicinal bromochlorination on an aryl-substituted allene was demonstrated.¹⁰

We sought to develop a strategy for the interhalogenation of terminal allenes by utilizing sulfinyl halides, thereby permitting catalyst control in the availability of the nucleophilic halide anion (Figure 1c). Based on our prior work and the studies of others, we surmised that a transient methylenehaliranium species (II) could be intercepted by a halide anion salt (III) generated through Lewis base activation of thionyl chloride or thionyl bromide.^6,11,12 This strategy would allow for the precise installation of two different halides across the three consecutive sp²-hybridized carbons of an allene to furnish dihalogenated product 2. To date, common methods employed for allene dihalogenation are either unselective or primarily feature linear product (3) selectivity with varying levels of stereoselectivity.^13,14

We commenced our investigations by surveying conditions for allene bromochlorination. When 4,5-hexadienylbenzene (1a) was subjected to thionyl chloride and a slight excess of N-bromosuccinimide (NBS) in the absence of a catalyst, only trace quantities of isomeric bromochlorides 2a and 3a were observed (Table 1, entry 1). Instead, a significant amount of undesired dibromination byproduct was observed. Under the same conditions, but in the presence of 1 mol% triphenylphosphine oxide, product was formed in 82% yield, favoring branched bromochloride 2a with a 13:1 regioisomeric ratio (rr) (entry 2).

Table 1.

Reverse Optimization of Allene Bromochlorination ^a

Entry	Variation from std. conditions	Conv. (%)	Yield (%)b	2a:3a
1	No OPPh3	75	6	-
2	None	>99	82	13:1
3	Using PhMe as solvent	73	50	12.5:1
4	Using CH2Cl2 as solvent	>99	73	12.5:1
5	PPh3 instead of OPPh3	86	73	11:1
6	DMAP instead of OPPh3	92	56	15:1
7	HMPA instead of OPPh3	98	85	18:1
8	TPPA instead of OPPh3	91	71	17:1
9	NBP instead of NBS	97	88	14:1
10c	DBDMH instead of NBS	95	58	12:1
11	HMPA and NBP	>99	93 d	17.5:1
12	Non-dried glassware, under air	>99	83	17:1

^aReactions were carried out under an atmosphere of N₂ using 0.2–0.3 mmol 1a (1.0 equiv). Reactions were run for a duration of 3-4 h. DMAP = 4-dimethylaminopyridine, HMPA = hexamethylphosphoramide, TPPA = tripyrrolidinophosphoric acid triamide, NBP = N-bromophthalimide, DBDMH = 1,3-dibromo-5,5-dimethylhydantoin.

^bYields and regiomeric ratios were determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene (0.1 mmol) as an internal standard.

^c0.52 equiv of DBDMH was used instead.

^dRepresents the isolated yield on a 1 mmol scale.

While various solvents were generally suitable, trifluorotoluene proved optimal with respect to reaction efficiency and selectivity (entries 2-4).¹⁵ A survey of Lewis base catalysts revealed triphenylphosphine oxide and hexamethylphosphoramide (HMPA) as superior catalysts, delivering up to 85% yield (18:1 rr) at minimal loadings (entries 5-8). In the examination of alternative bromenium sources, N-bromophthalimide (NBP) provided optimal results, particularly when used in combination with HMPA, affording bromochloride 2a in 93% yield with 17.5:1 rr (entries 9-11). Further, the reaction displays similar efficiency under non-inert conditions (entry 12).

With the optimized conditions established, we next examined the scope of this transformation (Table 2). In all cases, compound 2 was obtained as the major product, with varying levels of linear-to-branched regioselectivity. Monosubstituted allenes, both with and without alpha-branching substituents, provided similar regioisomeric ratios (rr), yielding branched dihalide products (2a, 2b, and 2d). Furthermore, the reaction demonstrated scalability, allowing for the isolation of 2.9 g of 2a with minimal loss of efficiency and selectivity. One exception, aryl allene 1c, resulted in both poor yield and selectivity, likely due to conjugation modulating the reactivity of the internal alkene. However, this strategy enabled the synthesis of the branched bromochloride product 2c as the major isomer, notably in contrast to previous methods that typically favor the formation of linear dihalide products.

Table 2.

Scope of Catalytic Allene Dihalogenation^a

^aUnless specified otherwise, reactions were carried out under a N₂ atmosphere on a 0.5–12.64 mmol scale (see the Supporting Information). Regiomeric ratios (rr) were determined by analysis of the ¹H NMR spectra of the purified products. Reported yields represent the combined mixture of regioisomers.

^bReaction was carried out without addition of catalyst.

^cReaction was carried out with 0.83 equiv NBP instead.

Allenes bearing a variety of functional groups were well-tolerated regardless of their proximity to the reactive site (2e–2m).¹⁶ In all cases, the desired products were obtained in good-to-high yields with generally high selectivity. Though many products were isolated with improved yield and/or selectivity using the HMPA/NBP conditions (2a, 2b, 2j, and 2m), some substrates (e.g., 1h and 1i) performed better with the OPPh3/NBS conditions instead. Furthermore, substrate 1k, which contains a Lewis basic phosphate substituent, did not require the addition of a catalyst.

By modifying the electrophilic and nucleophilic halogenating reagents to NIS and SOBr₂ or NIS and SOCl₂, a range of iodobrominated and iodochlorinated products were isolated (2n–2u), albeit with reduced selectivity. For comparison, optimization substrate 1a yielded iodobromide 2n in 87% yield with a 4:1 rr and iodochloride 2r in 88% yield with a 4.7:1 rr. Notably, although allene 1u, derived from the uric acid reducer probenecid, formed a crude product mixture with a 1.5:1 ratio of 2u to 3u, the branched product could be cleanly isolated, yielding iodochloride 2u as a pure isomer in 50% yield.

Historically, methods for the dibromination of allenes have been plagued by poor yields and/or selectivity.^{13b, 17} Therefore, we were interested in evaluating the selectivity of this catalytic manifold by comparison. Using NBP with thionyl bromide under the standard catalytic conditions developed here, the dibromination of allenes 1v–1y largely favored halogenation at the internal alkene, including substrates featuring substructures derived from marketed therapeutics (1w, 1y). These results demonstrate, in some cases, the orthogonal selectivity imparted by this catalyst-controlled strategy (see Supporting Information for additional examples).

To investigate the utility of these uncommon vicinal, vinylic, allylic heterodihalides in organic synthesis, we chose to explore the innate reactivity differences between each class of dihalide (Scheme 1).¹⁸ Focusing initially on bromochlorides 2a and 2b, we applied copper-catalyzed S_N2′ allylic alkylation, yielding 4a in 62% with an E/Z ratio >10:1.¹⁹ In contrast, S_N2 displacement proved more challenging, though acetate 4b was obtained in low yield.²⁰ To illustrate the utility of these products for consecutive functionalization, enolate alkylation to afford vinyl bromide 4c followed by Stille cross-coupling gave an overall two-step yield of 53% of ester 4d.

Scheme 1.

Diversification of Interhalides^a

^a Unless specified otherwise, reactions were carried out under a N₂ atmosphere. Regiomeric ratios (rr) were determined by analysis of the ¹H NMR spectra of the purified products. E/Z selectivity was determined via NOESY analysis. ^b Yield was determined by ¹H NMR spectroscopy of the crude reaction mixture, using mesitylene (0.1 mmol) as an internal standard. Conditions a: CuCN (5 mol%), EtMgBr (1.2 equiv), CH2Cl2 (0.1 M), −78 °C, 22–23 h. Conditions b: AcOK (7.0 equiv), 18-crown-6 (7.5 equiv), DMF (0.025 M), 23 °C, 21 h. Conditions c: n-BuLi (1.1 equiv), HNEt₂ (1.2 equiv), ethyl isobutyrate (1.0 equiv), THF (0.5 M), −78 °C to 23 °C, 22 h. Conditions d: Pd(PPh₃)₄ (5 mol%), 2-(tributylstannyl)furan (1.2 equiv), 1,4-dioxane (0.2 M), 100 °C, 15 h. Conditions e: NEt₃ (1.0 equiv), p-thiocresol (1.0 equiv), benzene (0.25 M), 12 h. Conditions f: CuI (5 mol%), Cs₂CO₃ (1.5 equiv), acetamide (1.2 equiv), N,N-dimethylethylenediamine (10 mol%), THF (0.33 M), 70 °C, 17 h. Conditions g: PhSO₂Na (4.0 equiv), Pd(PPh₃)₄ (5 mol%), DMSO (375 μL), THF (0.2 M), 60 °C, 17 h, Conditions h: AcOK (2.0 equiv), 18-crown-6 (2.5 equiv), DMF (0.3 M), 23 °C, 1 h.

Comparatively, the analogous iodochloride 2r demonstrated poorer selectivity both in the copper-catalyzed allylic alkylation (4e) and the direct substitution with KOAc (4f). A limitation of the iodohalides, in general, is their bench instability, necessitating rapid purification of the dihalide followed by immediate setup for subsequent diversification reactions. Nevertheless, iodobromide 2n exhibited superior S_N2′ reactivity with p-thiocresol (4g, 80% yield 1:5.7 E/Z) followed by copper-catalyzed amide coupling of the vinyl iodide to afford enamide 4h in 59% isolated yield. ^{21, 22}

As anticipated, vicinal vinylic, allylic dibromides proved to be the best compromise between the bromochlorides and the iodohalides, owing to the lability of the allylic bromide combined with the better stability of the vinyl bromide. Probenecid-derived dibromide 2y could undergo highly selective regiodivergent substitutions to afford vinyl bromides 4i and 4j in synthetically useful yields. Notably, palladium-catalyzed Tsuji-Trost substitution with benzenesulfinate was feasible without significant β-halo elimination to the allene, as observed with other dihalide variants.²³

In conclusion, we have developed a catalytic dihalogenation of monosubstituted allenes, leading to vicinal vinylic and allylic dihalides. Products were isolated in up to 93% yield and >20:1 regioselectivity using common electrophilic reagents in combination with thionyl halides as latent nucleophiles activated by simple Lewis base catalysts. This convenient strategy for the synthesis of bromochlorides, iodochlorides, iodobromides, and dibromides employs non-cryogenic reaction temperatures and low catalyst loadings of 1 mol%. The resulting dihalides were evaluated as useful building blocks for the preparation of a diverse range of functionalized di- and trisubstituted alkenes.

Supplementary Material

The Supporting Information is available free of charge on the ACS Publications website.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.